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Leukemia stem cells niche normal hematopoiesis

Juan Carlos Balandrán, Eduardo Vadillo, David Dozal, Alfonso Reyes-López, Antonio Sandoval-Cabrera, Merle Denisse Laffont-Ortiz, Jessica L Prieto-Chávez, Armando Vilchis-Ordoñez, Henry Quintela-Nuñez Del Prado, Héctor Mayani, Juan Carlos Núñez-Enríquez, Juan Manuel Mejía-Aranguré, Briceida López-Martínez, Elva Jiménez-Hernández, Rosana Pelayo
BACKGROUND AND AIMS: Childhood acute leukemias (AL) are characterized by the excessive production of malignant precursor cells at the expense of effective blood cell development. The dominance of leukemic cells over normal progenitors may result in either direct suppression of functional hematopoiesis or remodeling of microenvironmental niches, contributing to BM failure and AL-associated mortality. We undertook this study to investigate the contents and functional activity of hematopoietic stem/progenitor cells (HSPC) and their relationship to immune cell production and risk status in AL pediatric patients...
November 2016: Archives of Medical Research
Marco Carretta, Bauke de Boer, Jenny Jaques, Antonella Antonelli, Sarah J Horton, Huipin Yuan, Joost D de Bruijn, Richard W J Groen, Edo Vellenga, Jan Jacob Schuringa
Recently, NOD-SCID IL2Rγ(-/-) (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO)...
July 2017: Experimental Hematology
Kazuhito Naka, Atsushi Hirao
Throughout the lifetime of an individual, hematopoietic stem cells (HSCs) maintain the homeostasis of normal hematopoiesis through the precise generation of mature blood cells. Numerous genetic studies in mice have shown that stem-cell quiescence is critical for sustaining primitive long-term HSCs in vivo. In this review, we first examine the crucial roles of transforming growth factor β (TGF-β) and related signaling molecules in not only regulating the well-known cytostatic effects of these molecules but also governing the self-renewal capacity of HSCs in their in vivo microenvironmental niche...
February 13, 2017: Cold Spring Harbor Perspectives in Biology
Hind Medyouf
Similar to their healthy counterpart, malignant hematopoietic stem cells in myeloid malignancies, such as myeloproliferative neoplasms, myelodysplastic syndromes, and acute myeloid leukemia, reside in a highly complex and dynamic cellular microenvironment in the bone marrow. This environment provides key regulatory signals for and tightly controls cardinal features of hematopoietic stem cells (HSCs), including self-renewal, quiescence, differentiation, and migration. These features are essential to maintaining cellular homeostasis and blood regeneration throughout life...
March 23, 2017: Blood
Ander Abarrategi, Katie Foster, Ashley Hamilton, Syed A Mian, Diana Passaro, John Gribben, Ghulam Mufti, Dominique Bonnet
The BM niche comprises a tightly controlled microenvironment formed by specific tissue and cells that regulates the behavior of hematopoietic stem cells (HSCs). Here, we have provided a 3D model that is tunable in different BM niche components and useful, both in vitro and in vivo, for studying the maintenance of normal and malignant hematopoiesis. Using scaffolds, we tested the capacity of different stromal cell types to support human HSCs. Scaffolds coated with human mesenchymal stromal cells (hMSCs) proved to be superior in terms of HSC engraftment and long-term maintenance when implanted in vivo...
February 1, 2017: Journal of Clinical Investigation
Jennifer Enciso, Hector Mayani, Luis Mendoza, Rosana Pelayo
Lineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia (ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis...
2016: Frontiers in Physiology
Christine Roden, Jun Lu
Studies on hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have helped to establish the paradigms of normal and cancer stem cell concepts. For both HSCs and LSCs, specific gene expression programs endowed by their epigenome functionally distinguish them from their differentiated progenies. MicroRNAs (miRNAs), as a class of small non-coding RNAs, act to control post-transcriptional gene expression. Research in the past decade has yielded exciting findings elucidating the roles of miRNAs in control of multiple facets of HSC and LSC biology...
September 2016: Current Stem Cell Reports
Lisa Pleyer, Peter Valent, Richard Greil
Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts...
June 27, 2016: International Journal of Molecular Sciences
Hui Cheng, Tao Cheng
PURPOSE OF REVIEW: Mortality and morbidity associated with leukemia are largely due to frequently occurring cytopenias or the dysfunction of normal blood cells in patients. Our knowledge of how normal blood cells degenerate in response to leukemic cell infiltration has been quite limited. This review summarizes recent findings and discusses both extrinsic and intrinsic mechanisms underlying the suppression of normal hematopoiesis in leukemia. RECENT FINDINGS: Recent studies have shown that leukemic cells are able to remodel the bone marrow niche by secreting specific cytokines or dampening its hematopoietic-supporting functions...
July 2016: Current Opinion in Hematology
Jing Li, Jun Zhang, Minghui Tang, Junping Xin, Yan Xu, Andrew Volk, Caiqin Hao, Chenglong Hu, Jiewen Sun, Wei Wei, Quichan Cao, Peter Breslin, Jiwang Zhang
The phosphorylated form of Pten (p-Pten) is highly expressed in >70% of acute myeloid leukemia samples. However, the role of p-Pten in normal and abnormal hematopoiesis has not been studied. We found that Pten protein levels are comparable among long-term (LT) hematopoietic stem cells (HSCs), short-term (ST) HSCs, and multipotent progenitors (MPPs); however, the levels of p-Pten are elevated during the HSC-to-MPP transition. To study whether p-Pten is involved in regulating self-renewal and differentiation in HSCs, we compared the effects of overexpression of p-Pten and nonphosphorylated Pten (non-p-Pten) on the hematopoietic reconstitutive capacity (HRC) of HSCs...
August 2016: Stem Cells
Diana Passaro, Christine Tran Quang, Jacques Ghysdael
Intensive chemotherapy regimens have led to a substantial improvement in the cure rate of patients suffering from T-cell acute lymphoblastic leukemia (T-ALL). Despite this progress, about 15% and 50% of pediatric and adult cases, respectively, show resistance to treatment or relapse with dismal prognosis, calling for further therapeutic investigations. T-ALL is an heterogeneous disease, which presents intrinsic alterations leading to aberrant expression of transcription factors normally involved in hematopoietic stem/progenitor cell development and mutations in genes implicated in the regulation of cell cycle progression, apoptosis, and T-cell development...
May 2016: Immunological Reviews
Hiroto Horiguchi, Masayoshi Kobune, Shohei Kikuchi, Masahiro Yoshida, Masaki Murata, Kazuyuki Murase, Satoshi Iyama, Kohichi Takada, Tsutomu Sato, Kaoru Ono, Akari Hashimoto, Ayumi Tatekoshi, Yusuke Kamihara, Yutaka Kawano, Koji Miyanishi, Norimasa Sawada, Junji Kato
The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition...
April 2016: Haematologica
Weihuan Wang, Grant Zimmerman, Xiaoran Huang, Shuiliang Yu, Jay Myers, Yiwei Wang, Stephen Moreton, Joseph Nthale, Amad Awadallah, Rose Beck, Wei Xin, David Wald, Alex Y Huang, Lan Zhou
More than half of T-cell acute lymphoblastic leukemia (T-ALL) patients harbor gain-of-function mutations in the intracellular domain of Notch1. Diffuse infiltration of the bone marrow commonly occurs in T-ALL and relapsed B-cell acute lymphoblastic leukemia patients, and is associated with worse prognosis. However, the mechanism of leukemia outgrowth in the marrow and the resulting biologic impact on hematopoiesis are poorly understood. Here, we investigated targetable cellular and molecular abnormalities in leukemia marrow stroma responsible for the suppression of normal hematopoiesis using a T-ALL mouse model and human T-ALL xenografts...
March 15, 2016: Cancer Research
Yevgeniya Le, Sylvain Fraineau, Priya Chandran, Mitchell Sabloff, Marjorie Brand, Jessie R Lavoie, Rémi Gagne, Michael Rosu-Myles, Carole L Yauk, Richard B Richardson, David S Allan
PURPOSE: The role of bone marrow-derived mesenchymal stem/stromal cells (MSCs) in creating a permissive microenvironment that supports the emergence and progression of acute myeloid leukemia (AML) is not well established. We investigated the extent to which adipogenic differentiation in normal MSCs alters hematopoietic supportive capacity and we undertook an in-depth comparative study of human bone marrow MSCs derived from newly diagnosed AML patients and healthy donors, including an assessment of adipogenic differentiation capacity...
April 2016: Stem Cell Reviews
A-Reum Han, Ji Yoon Lee, Hee-Je Kim, Woo-Sung Min, Gyeongsin Park, Se-Hoon Kim
The bone marrow microenvironment (BMM) provides a protective niche that supports growth and survival of normal and leukemic hematopoietic stem cells. The SDF-1/CXCR4 interaction is critical for regulation of homing to and retention of hematopoietic cells in the bone marrow (BM), which leads to increased chemoresistance. SDF-1/CXCR4 plays pivotal roles in cross-interactions between blasts and the BMM to prevent retention and mobilization of leukemic cells, as well as in normal hematopoiesis including the development of immune cells...
December 2015: Oncology Reports
Bijender Kumar, Mayra Garcia, Jodi L Murakami, Ching-Cheng Chen
The hematopoietic stem cell (HSC) niche is composed of a complex set of stromal support cells that maintain HSCs and promote normal hematopoiesis. We now know that molecular changes within the hematopoietic niche contribute to leukemia development. Leukemia cells often reorganize the hematopoietic niche to promote and support their own survival and growth. Here we will summarize recent works that decipher the normal hematopoietic niche cellular components and describe how the leukemia-transformed niche contributes to hematological malignances...
March 2016: Biochimica et Biophysica Acta
Yusuke Saito, Kazuhiro Morishita
Acute myeloid leukemia (AML) with high ecotropic viral integration site-1 (EVI1) expression (EVI1high AML) is classified as a refractory leukemia with a poor prognosis. We identified G protein-coupled receptor 56 (GPR56) as a novel marker for EVI1high AML, which is an orphan adhesion G protein-coupled receptor (GPCR). GPR56 was found to be associated with high cell adhesion and anti-apoptotic activities in EVI1high AML through activation of RhoA signaling. Moreover, in Gpr56-/- mice, the number of hematopoietic stem cells (HSCs) in bone marrow was significantly decreased with proportional increases in the spleen and peripheral blood, reflecting extramedullary hematopoiesis...
April 2015: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Andrew G Evans, Laura M Calvi
Fueled by the growing interest in stem cell biology and the promise of regenerative medicine, study of the hematopoietic stem cell (HSC) microenvironment has provided critical insights into normal and malignant hematopoiesis. Notch receptor signaling in this microenvironment is a critical regulator of HSC fate and differentiation. Notch signaling also has the potential to modulate the growth of various malignant cell types, as evidenced by the growing list of hematologic cancers and other malignancies associated with either mutations in Notch genes or alterations in Notch signaling...
January 2015: Annals of the New York Academy of Sciences
Justin C Wheat, Daniela S Krause, Thomas H Shin, Xi Chen, Jianfeng Wang, Dacheng Ding, Rae'e Yamin, David A Sweetser
Hematopoiesis is a complex process that relies on various cell types, signaling pathways, transcription factors and a specific niche. The integration of these various components is of critical importance to normal blood development, as deregulation of these may lead to bone marrow failure or malignancy. Tle4, a transcriptional corepressor, acts as a tumor suppressor gene in a subset of acute myeloid leukemia, yet little is known about its function in normal and malignant hematopoiesis or in mammalian development...
2014: PloS One
Maria Krevvata, Barbara C Silva, John S Manavalan, Marta Galan-Diez, Aruna Kode, Brya Grace Matthews, David Park, Chiyuan A Zhang, Naomi Galili, Thomas L Nickolas, David W Dempster, William Dougall, Julie Teruya-Feldstein, Aris N Economides, Ivo Kalajzic, Azra Raza, Ellin Berman, Siddhartha Mukherjee, Govind Bhagat, Stavroula Kousteni
The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival...
October 30, 2014: Blood
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